Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity

Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using th...

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Veröffentlicht in:	PloS one Jg. 17; H. 9; S. e0273182
Hauptverfasser:	Pogacar, Ziva, Johnson, Jackie L., Krenning, Lenno, De Conti, Giulia, Jochems, Fleur, Lieftink, Cor, Velds, Arno, Wardak, Leyma, Groot, Kelvin, Schepers, Arnout, Wang, Liqin, Song, Ji-Ying, van de Ven, Marieke, van Tellingen, Olaf, Medema, Rene H., Beijersbergen, Roderick L., Bernards, Rene, Leite de Oliveira, Rodrigo
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	San Francisco Public Library of Science 06.09.2022 Public Library of Science (PLoS)
Schlagworte:	Analysis Breast cancer Cancer Cancer therapies Care and treatment Cell cycle Clinical trials Colorectal cancer Combined treatment Cyclin-dependent kinase 2 Cyclin-dependent kinase 4 Experiments Gene expression Genetic screening Inactivation Kinases Lung cancer Lung diseases Medicine and Health Sciences Metastases Morphology Research and Analysis Methods Senescence Tumor cell lines Xenografts Xenotransplantation Netherlands
ISSN:	1932-6203, 1932-6203
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Abstract	Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
AbstractList	Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition. Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition. Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6 inhibitor approved for treatment of metastatic breast cancer, we performed functional genetic screens in palbociclib-resistant cells. Using this approach, we found that loss of CDK2 results in strong senescence induction in palbociclib-treated cells. Treatment with the CDK2 inhibitor indisulam, which phenocopies genetic CDK2 inactivation, led to sustained senescence induction when combined with palbociclib in various cell lines and lung cancer xenografts. Treating cells with indisulam led to downregulation of cyclin H, which prevented CDK2 activation. Combined treatment with palbociclib and indisulam induced a senescence program and sensitized cells to senolytic therapy. Our data indicate that inhibition of CDK2 through indisulam treatment can enhance senescence induction by CDK4/6 inhibition.
Audience	Academic
Author	Jochems, Fleur Johnson, Jackie L. Beijersbergen, Roderick L. De Conti, Giulia Groot, Kelvin Pogacar, Ziva Wardak, Leyma Medema, Rene H. Bernards, Rene Velds, Arno van Tellingen, Olaf Song, Ji-Ying Wang, Liqin Leite de Oliveira, Rodrigo Krenning, Lenno Schepers, Arnout Lieftink, Cor van de Ven, Marieke
AuthorAffiliation	1 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 6 Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 7 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 The NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands 5 Division of Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 4 Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands University of Wisconsin-Madison, UNITED STATES
AuthorAffiliation_xml	– name: 4 Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 7 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 5 Division of Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 3 The NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 1 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: University of Wisconsin-Madison, UNITED STATES – name: 2 Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands – name: 6 Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: R.B is the founder of the company Oncosence (https://www.oncosence.com), which aims to develop senescence-inducing and senolytic compounds to treat cancer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Current Address: CRISPR Expertise Center, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Snippet	Inducing senescence in cancer cells is emerging as a new therapeutic strategy. In order to find ways to enhance senescence induction by palbociclib, a CDK4/6...
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SubjectTerms	Analysis Breast cancer Cancer Cancer therapies Care and treatment Cell cycle Clinical trials Colorectal cancer Combined treatment Cyclin-dependent kinase 2 Cyclin-dependent kinase 4 Experiments Gene expression Genetic screening Inactivation Kinases Lung cancer Lung diseases Medicine and Health Sciences Metastases Morphology Research and Analysis Methods Senescence Tumor cell lines Xenografts Xenotransplantation
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Title	Indisulam synergizes with palbociclib to induce senescence through inhibition of CDK2 kinase activity
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Volume	17
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